BIO 501The Biology of Cancer

Introduction to 501

Online: Intro501(NoTP)

Updated: January 10, 2015

NewsWeekOct. 26,

2009

Phenomenology of Cancer:What are the features that cancers

present in human populations?

Extent and Clinical Patterns of Cancers

Epidemiology of Cancers

Classification and Nomenclature

What do these features tell us about the basic biology of cancer?

What do these features tell us about Diagnosis, Management (therapy), and Prevention of Cancers?

What Models of Cancers Do We Actually Use in Cancer Biology and Cancer Medicine?

Neoplastic and Normal Cell Lines in CultureTransformed Normal CellsFreshly-derived Cancer CellsGenetically Engineered CellsEngineered Tissues (3-Dimensional Cell Cultures)Animal Models in Cancer Research and Cancer Medicine

(“Pre-Clinical Trials”)Inbred Animal ModelsVeterinary AnimalsAnimal-Human Engineered Hybrid Models

Clinical Cancer in PatientsClinical Trials (Phase I, Phase II, and Phase III)

What are Cancer Cells Like?As Isolated Cells?

In Tumor-bearing Animals?In Patients?

Characteristics of Cancer Cells in CultureHow does a Cancer Cell “Talk” to Itself and Its Neoplastic Neighbors?

Why are cancer cells in cell culture Immortal?Tumor Cell Populations and Tumor Tissues in vivo

How do Cancer Cells “Talk” to each other? How do Cancer Cells “Talk” to normal cells?

What do cancer cells “hear” from the host?Why don’t cancer cells know how old they are and when to die?

Growth Patterns of Experimental and Clinical CancersHow Do Cancer Cells Change and Progress in Malignant Potential?

What are the Patterns of Invasion & Spread to Distant Sites?

What are Cancers like in Patients?What do clinicians see?

What are they dealing with?

The Story of Kuyler Van Nocker and Neuroblastoma(See Slide 49 for Video Link)

William Bunn: Boy Police-Officer and Neuroblastoma(See Slide 24 for Video Link)

Kelley Mitchell and Ewing’s Sarcoma(See Slide 50)

Taylor Black and NeuroblastomaSee UntreedReads.comDaydreams and Diaries

By Tim Black (Taylor Black’s Father)

What Features are Seen in Cancer Genetics?

What does modern genomics tell us about cancer biology, origins of cancer, cancer diagnosis and treatment?

What are the crucial features of cancer cell genomes?

What are the hereditary patterns in tumor-bearing hosts?

What are the clonal origins of cancers?

What do Proteomics (the spectrum of expressed proteins) and Epigenetics* tell us about Cancer origins and

progression?*(modification of genes and gene-products)

Differentiation and Cancer:Cancer as an expression of abberrant

differentiation

How are genes expressed and controlled in cancer?

Can the malignant state be reversed to normal?

Why are oncofetal genes often re-expressed in cancers?

Biological Mechanisms Underlying Cancer Phenomenology

Cell Cycle, Proliferation, Signalling, and ImmunogenicityCellular Senescence, Immortalization, and Cancer

Cell Death (Genetically-programmed cell death; Apoptosis)Telomeres and Cell Ageing

Autophagy (Inter-cellular “cannibalism”) and CancerIntra-cellular signaling

Growth Factors and ReceptorsInter-cellular Communication

Cell MovementGene Expression and Differentiation Control

Normal Immune Responses and Immune EscapeProtein Structure, Function, and Modification

Onco-fetal gene products

Basic Biology in the Diagnosis and Therapy of Cancers

Modalities in Cancer Management

Host Response Modifiers

Genetics and Cancer Management

Immunotherapy & Immunodiagnosis of Cancers

Cancer Chemotherapy

New Approaches to Cancer ManagementSpecific Targeted Therapy

(See Slides 42, Molecular Signaling in Cancer & Slide 43, The RAS Pathway

for an examples of a cell signaling pathways in cancer.

“Phenotherapy” of Cancer?

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_______________________________________________________________

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Type in your message. I will get an icon on my screen to see what was asked.

To Respond to Turning Point Questions in Class:Using the NXT Transmitter

(Revised January 10, 2015

1. Put your last name onto your transmitter under “Your ID” for NXT 2. If you borrow a transmitter from us, fill out an index card, take instruction form, leave the

device ID unchanged on the borrowed transmitter. We will know who y ou are form the index card that you filled out on the date when you borrowed our transmitter. Do not change the “BIO” designation.

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4. Respond to the question as directed on the question itself.5. With NXT you have to hit the square response button in the upper left below the screen in

order to get to the blank screen that is presentation mode.6. Screen will show whether your response has been received. Your device will also show a check

when your name has been received.7. If you have problem with your NXT transmitter we can provide a paper back-up form if

absolutely unavoidable. However, you must hand in the back-up form with your response at the same time that the question is being responded to by the rest of the class.

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9. We count persons in class and match that number with the TP responses + Backup Forms. 10. If the numbers don’t agree, we hand out paper forms one-at-a-time. The person or persons

who have someone else respond for them will be dismissed from the class

The Next Two Slides are Turning Point Quiz Question Slides

You may not use any notes or electronic devices other than your NXT transmitter. No computers. No phones. No talking or consulting.

Make sure that your desk is clear.

These are graded quizzes that make up 40% of the overall course grade.

They are designed for both you and me to determine whether you are paying attention and following what is going on.

You can send a “Response to Leader” while a TP Slide is open. Give it a try. You can communicate with me.

With your name entered under Device ID:To get a blank screen that accepts your response:

repeatedly push the black square button in the upper left of the NXT device. When you get the blank screen,

respond to the question:

I am here!

1. 2.

0%0%

1. Yes

2. No

Response

Counter

Course Evaluation, Grading,and Maintenance of Standards

Three In-Class Exams, 100 Pts EachTuesday February 17th, After Classes 1 to 10

Tuesday, March 31st, After Classes 11 to 19

Tuesday April 28th, after Classes 20 to 27(Last Day of Class)

Class Participation Components at Every Class:

Based on Responses Using Turning Point NXT-Transmitters

200 Points Maximum Possible (40% of Course Grade)

Course Web-SiteIntegrated Web-site at

http://tpfondy.syr.edu/bio501

is a crucial element of this course.

See Class Schedule and Graphics

On Course Main Web-Page

To Send in a “Response to Leader” Question at any time during class:Use Cntrl F8.

(Your ID but not your name will show)

Type in your message. I will get an icon on my screen to see what was asked.

Textbook:Biology of Cancer

Robert A. WeinbergGarland Science, 2014

Second Edition

CD with Movies, Mini-lectures, Pathways in Cancer Poster,

Powerpoint and JPEG Versions of Textbook Graphics

501Text

Scope of Disciplines in Basic Sciences Involved in Biology of Cancer

Cell BiologyGeneticsMolecular BiologyBiochemistryImmunologyMicrobiology/VirologyDevelopmental BiologyPhysiologyEnvironmental Biology

HistologyPathobiologyPharmacologyEpidemiologyNeurobiologyOrganic ChemistryPhysicsStatisticsComputer Information Sciences

Some Conceptual Goals in Biology of Cancer Course

Overview of Cancer Biology: What Does One Study?How Do Cancer Biologists Think? How Are Questioned Formulated? How are Experiments and Trials Designed? What (Who) Do Cancer Biologists Work On?What are the Real Questions and the Limitations?What are the Currently Best Prospects for: Improved Understanding of the Biology of Cancer? Improved Diagnosis, Management, and Cures?What Do Terms in Oncology Mean?What is Cancer Like: As a Biological Manifestation? As a Clinical Problem? As a Problem for People?

Why Study the Biology of Cancer?

Cancer Incidence, Morbidity, and Mortality• 1,638,910 New Cases 2012- US; 1,660,290 (2013); 1,665,540 (2014)• ~12,000,000 New Cases per Year - World-Wide• 580,350 Deaths 2013- US ; 585,720 (2014)• 1,590 Deaths per Day – 2013 U.S. ; 1,605 (2014) • ~6,000,000 Deaths per Year - World-Wide• 1 in 200 out of 310 Million (US) will present with Cancer in 2014• Lifetime Risk of presenting with Cancer ~ 40%• (assuming 80-year lifespan and no change in incidence• 1 in 600 will die of Cancer in 2014 (0.18% of US Population)• Lifetime Risk of Death ~13%• Protracted, Degenerative, Dehumanizing Diseases• 1.8% of Cancer Deaths are Children ages 1 to 14

(10,800 deaths per year)

Cancer in Children

William Bunn: 8-Year-old Police OfficerJuly, 2010Filename: BoyPoliceman11July10.doc Video 1http://abclocal.go.com/wtvd/story?section=news/local&id=7531763  -  2 minutes and 32 seconds   Video 2http://www.msnbc.msn.com/id/26184891/vp/38084943#38084943   1 1/2 minutes - actual funeral Refers to Stem Cell Transplants and Chemotherapy for Neuroblastoma in final 5 seconds of clip

Video 3: Kuyler Van Nocker and Neuroblastoma (Slide 49)http://www.msnbc.msn.com/id/3036677/#39049661

Cancer and Other Causes of Death in Children

Number of Children 0 to 5 Years Old: 25.7 Million6 to 11 Years Old 25.0 Million12 to 17 Yrs Old 25.4 Million

Cancer Deaths in Children 140 per million children/year75 Million Children = 10,500 Cancer Deaths per Year1.8 % of total Cancer Deaths per Year

Gun Deaths in Children Ages 0 to 14 per Year:3,400 Gun Deaths per Year

(Accidental and Deliberate Homicide)School Shootings per Year Tripled since 1995

Sharpton News; January 16, 2013116,000 Guns Deaths in Children since 1979

How This Course in Cancer Biology is Set Up

Part 1: What is Cancer like as a collection of diseases?(Topics: Intro501; Clinical Patterns, Epidemiology, Classifications,

Model Systems)

Part 2: How do Cancers get that way?(Topics: Cancer Cell Properties, Cancer Cell Interactions, Progression, Growth, Invasion and Metastasis, Cancer Genetics, Cancer Virology)

Part 3: What can we do about it?(Topics: War on cancer 1972-2014, Cancer Therapy, Cancer Immunology,

Immunotherapy of Cancer; Clinical Management

Why Study the Biology of Cancer?

Biology as the Basis For:Improved Diagnosis

Improved ManagementIncreased Survival Time

Long-Term CuresPrevention

Chance for cure or extended survivaldepends strongly on where patient goes for

diagnosis and where patient is treated!(See Newsweek, Oct. 26, 2009)

“What You Don’t Know Might Kill You,

Why Biology of Cancer Now? The Knowledge Base

Advances in Molecular Genetics• Genomics and ProteonomicsCellular and Humoral ImmunityInter-cellular Communication and Regulation• Cytokines, Growth Factors, ReceptorsMembrane Structure and Function• Membrane Adhesion Receptors and Ligands• Membrane TransportIntra-cellular Pathways and Regulatory Cascades• Cell Cycle Control• Regulation of Nuclear Gene Expression• Normal and Aberrant Differentiation• Pathways to Cell Death or to Cellular Immortalization

BioKnow

Biotechnology & the Cancer Problemthe Technological Tools Now Available

Genetics, Cell, and Molecular Biology• Gene Identification, Isolation, Cloning, & Sequencing• Structure, Relationships, & Functions of Gene Products• Directed Protein Synthesis, Site-Directed MutagensisCell Separation and Cell Culture• In Situ Cell Labelling and Dynamic Functions• Cellular and Humoral Immunity• Monoclonal Antibodies• Radio-immunoassays• In Situ Labelling and DiagnosisBiophysical Tools• Magnetic Resonance, CAT Scan, X-Ray• Radio-isotope Labelling• Electron MicroscopyLive Animal Models and Tumor Model Systems• Inbred Animals• Genetically Engineered Animals BioTools

Molecular and Cellular Anomalies in Cancer

Abberant Genes and Gene Expression

Figure 1.11a The Biology of Cancer (© Garland Science 2007)

Banding pattern of normal metaphase human chromosomes

Figure 1.11b The Biology of Cancer (© Garland Science 2007)

Fluorescent in situ hybridization (FISH) of normal metaphase human chromosomes

using chromosome specific DNA probes with different fluorescent dyes

Figure 1.12a The Biology of Cancer (© Garland Science 2007)

Aneuploidy in Human Hepatocellular Carcinoma Cell Line

Hsr = homogeneously staining region due to endoreduplication of chromosomal segments resulting in gene amplification

Figure 1.11c The Biology of Cancer (© Garland Science 2007)

Aneuploid karyotype of human breast cancer cell.

Note “scrambling” of colors demonstrating chromosomal reciprocal translocations

Figure 1.11d The Biology of Cancer (© Garland Science 2007)

Intra-chromosonal inversion by M-band fluorescent in situ hybridization(mFISH)

Figure 1.18 The Biology of Cancer (© Garland Science 2007)

1800 HumanGenes

mRNA’s From 142 different human tumors

Red = elevated expression

Green = diminished expression

Gene Expression DNA Array Analysis

Molecular and Cellular Anomalies in Cancer

Aberrant Cell Structures and Cell Behavior

Role of the CytoskeletonIn Cell Adhesion, Cell Division, Cell

Migration

Figure 1.14a The Biology of Cancer (© Garland Science 2007)

Cytoskeleton:

Actin microfilaments

Microtubules

Intermediate filaments

Figure 1.14b The Biology of Cancer (© Garland Science 2007)

Intermediate Filaments of epithelial cell (keratin) in green

Plasma membrane in blue

Figure 1.14d The Biology of Cancer (© Garland Science 2007)

3T3 Mouse Fibroblast attached to fibronectin extra-cellular matrix by integrin receptors

Figure 1.15c The Biology of Cancer (© Garland Science 2007)

Motility of a Fish Keratocyte

Actin microfilament leading edge

Why is Cancer This Way?

What can we do about it?

The Complexity of Signaling Factors, Receptors, and

Pathways

R

T

K

R

T

K

Ras Pathway

SHC

GDP

GTP CD-GEGIIGAP

GTP

Elk1

c-FosATF2

c-Jun

Actin

Cytosk

elet

on

PP P

P

P

P

Stress Fibers and Focal AdhesionsStress Fibers and Focal Adhesions

GeneExpression

GeneExpression

PLDPathway

PLDPathway

PMAPMA

Growth FactorsGrowth FactorsIncreased T Cell

AdhesionIncreased T Cell

Adhesion

IntegrinsIntegrins

β1β1β2β2 β2β2

β1β1β1β1SOS

p120-GAP

p190-B

Rho

PI3KPLC-ε

Rap1A

PLD RalBP1

PAKs

ERKs

ERKs

JNKK

JNKJNK

MEKK1

CDC42

Rac

MEKs

RafRalGDS

Ral

GRB2

TC

R

TC

R

AntigenAntigen

LckGEF

Ras Ras

2009ProteinLounge.com 2009ProteinLounge.com

C

Growth Factors and Receptors:Signal Transduction Across Membranes

Molecular Signaling in Cancer (From Quigen.com)

Thoughts on Conversations in a

Crowded Room

The Next Two Slides are Turning Point Quiz Question Slides

You may not use any notes or electronic devices other than your NXT transmitter. No computers. No phones. No talking or consulting.

Make sure that your desk is clear.

These are graded quizzes that make up 40% of the overall course grade.

They are designed for both you and me to determine whether you are paying attention and following what is going on.

You can send a “Response to Leader” while a TP Slide is open. Give it a try. You can communicate with me.

About Kuyler Van Nocker

and

Neuroblastoma

http://www.msnbc.msn.com/id/3036677/#39049661

Cancer Biology and Clinical TreatmentThe Impact of the Health-care System

Cancer Treatment | PBS NewsHour | Jan. 1, 2001 | PBSJan 1, 2001 ... ELIZABETH BRACKETT: Last year, Kelley Mitchell lost her battle against cancer. But before the 16-year-old died, she agreed to try a highly ...www.pbs.org/newshour/bb/health/jan-june01/cancer_01-01.html

Week Two: The Story of Kelley Mitchell and Ewings Sarcoma

Last Presentation: The Story of Taylor Black and Neuroblastoma(“Daydreams and Diaries” - UntreedReads.comOnLine Story of Taylor Black by Tim Black)

Intro501 Stops Here for 2014

Go to: Cancer2013_ACS.pptx

American Cancer Society Facts and Figures for 2014

On a scale of 1 to 5 rate:#1 = -2 = I’m pretty much lost, Please slow down and repeat.

#2 = -1 = I’m struggling. I follow some of it, but I’m having hard time.#3 = 0 = I’m OK. I understand most of it. I’ll figure the rest out later.

#4 =+1 = I doing OK. No Problem.#5 = +2 = This is no sweat. Please get moving before I get totally bored.

1

2

3

4

5

Duration: 5 Seconds

Figure 1.21 The Biology of Cancer (© Garland Science 2007)

Gene Cloning in a Bacterial Vector

Figure 1.19 The Biology of Cancer (© Garland Science 2007)

Regulation of Gene Expression by Transcription Factors:

General and Specialized Transcription Factors